The senescence-associated secretory phenotype: the dark side of tumor suppression.

Abstract

Cellular senescence is a tumor-suppressive mechanism that permanently arrests cells at risk for malignant transformation. However, accumulating evidence shows that senescent cells can have deleterious effects on the tissue microenvironment. The most significant of these effects is the acquisition of a senescence-associated secretory phenotype (SASP) that turns senescent fibroblasts into proinflammatory cells that have the ability to promote tumor progression.

Multiple types of stimuli can provoke cellular senescence and a senescence-associated secretory phenotype (SASP). When irreversible cell-cycle arrest is triggered by severe DNA damage (i.e., dysfunctional telomeres or oncogenic stress), the SASP occurs in senescent cells. However, when a senescent-like phenotype is triggered in cells that overexpress cell-cycle inhibitors such as p16 or p21, cells undergo a growth arrest with many characteristics of senescent cells, but not a SASP.

Human fibroblasts, either presenescent (PRE) or senescent (SEN), were immunostained for the inflammatory cytokines interleukin (IL)-6 and IL-8, as well as the senescence marker p16. Cells were made senescent either by replicative exhaustion (REP) or ionizing radiation (IR) or by expression of oncogenic RAS (RAS).

The DNA damage signaling pathway leads to the activation of the p53 tumor suppressor. Activated p53 triggers cell fate decisions, such as senescence or apoptosis. Depending on the cell context, p53 can suppress cancer through transient cell-cycle arrest and activation of the DNA-repair machinery. Additionally, p53 restrains the senescence-associated secretory phenotype (SASP). Regulation of the SASP by p53 suggests a cell-nonautonomous function of this tumor suppressor. In the short term, the SASP may promote tissue repair. In the long term, it may promote chronic inflammation, which in turn can drive cancer and aging.